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Nanotoxicology at the particle/micelle frontier: influence of core-polymerization on the intracellular distribution, cytotoxicity and genotoxicity of polydiacetylene micelles.
Nanoscale ( IF 5.8 ) Pub Date : 2020-01-09 , DOI: 10.1039/c9nr08714a Federica Costamagna 1 , Hervé Hillaireau 1 , Juliette Vergnaud 1 , Damien Clarisse 2 , Lucie Jamgotchian 2 , Olivier Loreau 2 , Stéphanie Denis 1 , Edmond Gravel 2 , Eric Doris 2 , Elias Fattal 1
Nanoscale ( IF 5.8 ) Pub Date : 2020-01-09 , DOI: 10.1039/c9nr08714a Federica Costamagna 1 , Hervé Hillaireau 1 , Juliette Vergnaud 1 , Damien Clarisse 2 , Lucie Jamgotchian 2 , Olivier Loreau 2 , Stéphanie Denis 1 , Edmond Gravel 2 , Eric Doris 2 , Elias Fattal 1
Affiliation
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The understanding of the cellular uptake and the intracellular fate of nanoparticles and their subsequent influence on cell viability is challenging as far as micelles are concerned. Such systems are dynamic by nature, existing as unimers under their critical micelle concentration (CMC), and as micelles in equilibrium with unimers above the CMC, making canonical dose-response relationships difficult to establish. The purpose of this study was to investigate the in vitro cytotoxicity and uptake of two micellar sytems that are relevant for drug delivery. The two micelles incorporate a poly(ethylene glycol) coating and a pentacosadiynoic core which is either polymerized (pDA-PEG micelles) or non-polymerized (DA-PEG micelles), with the aim of evaluating the influence of the micelles status ("particle-like" or "dynamic", respectively) on their toxicological profile. Intracellular distribution and cytotoxicity of polymerized and non-polymerized micelles were investigated on RAW 264.7 macrophages in order to compare any different interactions with cells. Non-polymerized micelles showed significantly higher cytotoxicity than polymerized micelles, especially in terms of cell permeabilization, correlated to a higher accumulation in cell membranes. Other potential toxicity endpoints of polymerized micelles were then thoroughly studied in order to assess possible responses resulting from their endocytosis. No specific mechanisms of cytotoxicity were observed, neither in terms of apoptosis induction, cell membrane damage, release of inflammatory mediators nor genotoxicity. These data indicate that non-polymerized micelles accumulate in the cell membrane and induce cell membrane permeabilization, resulting in significant toxicity, whereas polymerized, stable micelles are internalized by cells but exert no or very low toxicity.
中文翻译：
粒子/胶束前沿的纳米毒理学：核心聚合对聚二乙炔胶束的细胞内分布，细胞毒性和遗传毒性的影响。
就胶束而言，对纳米颗粒的细胞摄取和细胞内命运及其对细胞生存力的后续影响的理解具有挑战性。这种系统本质上是动态的，在其临界胶束浓度（CMC）下以单聚体形式存在，并且与CMC上方的单聚体处于平衡状态时形成胶束，从而难以建立规范的剂量反应关系。这项研究的目的是调查与药物传递有关的两个胶束系统的体外细胞毒性和摄取。这两个胶束包含一个聚乙二醇涂层和一个可聚合（pDA-PEG胶束）或未聚合（DA-PEG胶束）的戊二醛基核，目的是评估胶束状态（“粒子” -“”或“动态”，分别在其毒理学特征上）。为了比较与细胞的任何不同相互作用，在RAW 264.7巨噬细胞上研究了聚合和非聚合胶束的细胞内分布和细胞毒性。非聚合的胶束显示出比聚合的胶束显着更高的细胞毒性，特别是在细胞通透性方面，与细胞膜中更高的积累有关。然后对聚合胶束的其他潜在毒性终点进行了彻底研究，以评估其内吞作用可能引起的反应。没有观察到特定的细胞毒性机制，无论是在细胞凋亡诱导，细胞膜损伤，炎性介质释放还是遗传毒性方面。
更新日期：2020-01-09
中文翻译：
粒子/胶束前沿的纳米毒理学：核心聚合对聚二乙炔胶束的细胞内分布，细胞毒性和遗传毒性的影响。
就胶束而言，对纳米颗粒的细胞摄取和细胞内命运及其对细胞生存力的后续影响的理解具有挑战性。这种系统本质上是动态的，在其临界胶束浓度（CMC）下以单聚体形式存在，并且与CMC上方的单聚体处于平衡状态时形成胶束，从而难以建立规范的剂量反应关系。这项研究的目的是调查与药物传递有关的两个胶束系统的体外细胞毒性和摄取。这两个胶束包含一个聚乙二醇涂层和一个可聚合（pDA-PEG胶束）或未聚合（DA-PEG胶束）的戊二醛基核，目的是评估胶束状态（“粒子” -“”或“动态”，分别在其毒理学特征上）。为了比较与细胞的任何不同相互作用，在RAW 264.7巨噬细胞上研究了聚合和非聚合胶束的细胞内分布和细胞毒性。非聚合的胶束显示出比聚合的胶束显着更高的细胞毒性，特别是在细胞通透性方面，与细胞膜中更高的积累有关。然后对聚合胶束的其他潜在毒性终点进行了彻底研究，以评估其内吞作用可能引起的反应。没有观察到特定的细胞毒性机制，无论是在细胞凋亡诱导，细胞膜损伤，炎性介质释放还是遗传毒性方面。
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